The physiological functions of IKKs-selective substrateidentification and their critical roles in diseases

Abstract

The nuclear factor κB (NF-κB) transcription factors exert central hub functions in multiple physiological processes including immune response, cell survival, proliferation and cytokine production, which has naturally become the core of research almost in all aspects of biomedical science over 30 years. Since both the activation and termination of NF-κB pathway are tightly regulated, little alteration can lead to excessive inflammatory responses and even result in tissue damage and severe diseases. The inhibitor of nuclear factor kappa-B (IκB) kinase (IKK) complex is the main regulator of the NF-κB signaling pathway,they mediate and deliver signals through phosphorylating certain substrates. In recent years, increased proteins have been identified to be targeted by IKK members and the particular modification mechanism becomes clear with the development of detecting techniques and structural biology. In this review, we summarize the known substrates of IKK family members either relevant or irrelevant to NF-κB signaling,their structures and phosphorylation patterns, and the related physiologic and/or pathologic responses.Understanding the regulation of IKKs on their substrates may be helpful to connect IKKs with specific signaling pathways or physiological phenomena, and is essential for targeting IKKs in clinical research.